De novo and bi-allelic variants in AP1G1 cause neurodevelopmental disorder with developmental delay, intellectual disability, and epilepsy.
De novo and bi-allelic variants in AP1G1 cause neurodevelopmental disorder with developmental delay, intellectual disability, and epilepsy.
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AP1G1 的从头变异和双等位基因变异会导致神经发育障碍，包括发育迟缓、智力障碍和癫痫。
DOI：
10.1016/j.ajhg.2021.05.007
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发表时间：
2021
影响因子：
9.8
通讯作者：
Krau
中科院分区：
文献类型：
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作者：
Usmani,MuhammadA;Ahmed,ZubairM;Magini,Pamela;Pienkowski,VictorMurcia;Rasmussen,KristenJ;Hernan,Rebecca;Rasheed,Faiza;Hussain,Mureed;Shahzad,Mohsin;Lanpher,BrendanC;Niu,Zhiyv;Lim,Foong-Yen;Pippucci,Tommaso;Ploski,Rafal;Krau
衔接蛋白（AP）复合物介导选择性胞内囊泡运输和极化定位的体树突蛋白在神经元中。AP复合物的各种亚基的致病等位基因与几种可遗传的人类疾病有关，包括智力残疾（ID）。在这里，我们报告两个双等位基因（c.737C>A [p.Pro246His]和c.1105A>G [p.Met369Val]）和8个新杂合变体（c.44G>A [p.Arg15Gln]，c.103C>T [p.Arg35Trp]，c.104G>A [p.Arg35Gln]，c.229delC [p.Gln77Lys 11]，c.399_400del [p.Glu133Aspfs p.37]，c.747G>T [p.Gln249His]，c.928−2A>C [p.？]，和c.2459C>G [p.Pro820Arg]），编码接头相关蛋白复合物1（AP 1 γ1）的γ 1亚基，与神经发育障碍（NDD）相关，该疾病在11个不同种族的家系中表现为轻度至重度的ID、癫痫和发育迟缓。AP 1 γ1介导的接头复合物是网格蛋白包被的胞内囊泡形成的关键，计算机模拟和三维蛋白质建模模拟预测错义突变体的AP 1 γ1蛋白折叠发生改变，这与异源细胞中观察到的AP 1 γ1水平改变一致。对receptor遗传性错义变体的功能研究显示，对AP 1 γ1与AP-1复合物的其他亚基的相互作用没有明显影响，但显示影响内体再循环途径。敲除ap 1g 1在斑马鱼中导致严重的形态缺陷和致死性，这是显着拯救注射野生型AP 1G 1 mRNA，而不是由转录编码的错义变体。此外，显微注射野生型斑马鱼的mRNAs与de novomissense变体导致严重的发育异常和增加的致死率。我们的结论是，在不同的人群中，AP 1G 1的新生和双等位基因变异与神经发育障碍有关。
Adaptor protein (AP) complexes mediate selective intracellular vesicular trafficking and polarized localization of somatodendritic proteins in neurons. Disease-causing alleles of various subunits of AP complexes have been implicated in several heritable human disorders, including intellectual disabilities (IDs). Here, we report two bi-allelic (c.737C>A [p.Pro246His] and c.1105A>G [p.Met369Val]) and eightde novoheterozygous variants (c.44G>A [p.Arg15Gln], c.103C>T [p.Arg35Trp], c.104G>A [p.Arg35Gln], c.229delC [p.Gln77Lys∗11], c.399_400del [p.Glu133Aspfs∗37], c.747G>T [p.Gln249His], c.928−2A>C [p.?], and c.2459C>G [p.Pro820Arg]) inAP1G1, encoding gamma-1 subunit of adaptor-related protein complex 1 (AP1γ1), associated with a neurodevelopmental disorder (NDD) characterized by mild to severe ID, epilepsy, and developmental delay in eleven families from different ethnicities. The AP1γ1-mediated adaptor complex is essential for the formation of clathrin-coated intracellular vesicles.In silicoanalysis and 3D protein modeling simulation predicted alteration of AP1γ1 protein folding for missense variants, which was consistent with the observed altered AP1γ1 levels in heterologous cells. Functional studies of the recessively inherited missense variants revealed no apparent impact on the interaction of AP1γ1 with other subunits of the AP-1 complex but rather showed to affect the endosome recycling pathway. Knocking outap1g1in zebrafish leads to severe morphological defect and lethality, which was significantly rescued by injection of wild-typeAP1G1mRNA and not by transcripts encoding the missense variants. Furthermore, microinjection of mRNAs withde novomissense variants in wild-type zebrafish resulted in severe developmental abnormalities and increased lethality. We conclude thatde novoand bi-allelic variants inAP1G1are associated with neurodevelopmental disorder in diverse populations.